Quantitative Targeted Proteomics of Pancreatic Cancer: Deoxycytidine Kinase Protein Level Correlates to Progression-Free Survival of Patients Receiving Gemcitabine Treatment

Ken Ohmine, Kei Kawaguchi, Sumio Ohtsuki, Fuyuhiko Motoi, Hideo Ohtsuka, Junichi Kamiie, Takaaki Abe, Michiaki Unno, Tetsuya Terasaki

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

The purpose of the present study is to identify the determinant(s) of gemcitabine (dFdC)-sensitivity in pancreatic cancer tissues of patients treated with dFdC alone and in pancreatic cancer cell lines exposed to dFdC in vitro. Protein expression levels of 12 enzymes and 13 transporters potentially involved in transport and metabolism of dFdC in pancreatic cancer cell lines and tissues were quantified by means of our LC-MS/MS-based quantitative targeted proteomics technology. Protein expression levels of deoxycytidine kinase (dCK), uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase, cytosolic nucleotidase III (cN-III), and equilibrative nucleoside transporter 1 (ENT1) were significantly correlated with IC50 or 1/IC50 in five cell lines with different sensitivities to dFdC (p < 0.05). Expression levels of the selected proteins in pancreatic cancer tissues of 10 patients with different progression-free survival (PFS) (49-955 days) were quantified, and their relationship with PFS was examined. Only the protein expression level of dCK was significantly correlated with PFS (p < 0.05). Multiple regression analysis was also performed, and combinations of ENT1, UMP-CMP kinase, CTPS1, and dCK were highly correlated with PFS. Our results indicate that the protein expression level of dCK in pancreatic cancer tissue is a good predictor of PFS, and thus dCK may be the best biomarker of dFdC sensitivity in pancreatic cancer patients treated with dFdC, although other proteins would also contribute to dFdC-sensitivity at the cellular level in vivo and in vitro.

Original languageEnglish
Pages (from-to)3282-3291
Number of pages10
JournalMolecular pharmaceutics
Volume12
Issue number9
DOIs
Publication statusPublished - 2015 Sep 8

Keywords

  • deoxycytidine kinase
  • drug resistance
  • gemcitabine
  • pancreatic cancer
  • targeted proteomics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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